Abstract 559: FTY720 Protects Against Diet Induced Coronary Artery Disease and Myocardial Infarction in Diabetic SR-B1-/- ApoE-Hypomorphic Mice

Background: Epidemiological studies have established diabetes as a risk factor for the development of cardiovascular diseases. Increased development of aortic atherosclerosis has been shown in diabetic animal models, but the effect on coronary artery (CA) disease is less clear. Conventional mouse models of atherosclerosis do not reproducibly develop CA atherosclerosis. SR-B1-/- apoE-hypomorphic mice develop increased aortic sinus atherosclerosis and diet-induced CA atherosclerosis when compared to SR-B1+/+ apoE-hypomorphic mice. FTY720, a sphingosine-1-phosphate analog, has been shown to play a protective role in both atherosclerosis and diabetes. We assessed the hypothesis that FTY720 supplementation will decrease the development of CA and aortic atherosclerosis and myocardial infarction in diabetic SR-B1-/- apoE-hypomorphic mice fed an atherogenic diet. Methods: Diabetes was induced by multiple low-dose i.p. injections of streptozotocin (40 mg/kg body weight). Controls received vehicle. Mice were fed a high-fat/high-cholesterol diet for 4 weeks (n=14-15). FTY720 was administered on the drinking water (0.0036 g/l, n=14-15). CA and aortic atherosclerosis and cardiac fibrosis were evaluated. Results: Diabetic SR-B1-/- apoE-hypomorphic mice fed a high-fat/high-cholesterol diet presented reduced survival (p<0.01) and significantly larger plaques in the aortic sinus (p<0.05) compared to control. CA atherosclerosis burden (p<0.001) and levels of cardiac fibrosis (p<0.01) were increased as well. FTY720 supplementation significantly protected diabetic mice against aortic and CA atherosclerosis (p<0.05) and myocardial fibrosis (p<0.05). Conclusion: FTY720 significantly reduced the burden of aortic and CA atherosclerosis and cardiac fibrosis in diabetic SR-B1-/- apoE-hypomorphic mice challenged with a high-fat/high-cholesterol diet.